Project Summary: This project aims to understand the aging process in the lung beyond the phenotypic consequences. In both human and mouse, the loss of gas exchange surface area in aged lungs mirrors that of emphysema. The specific cells involved in the lung age-related loss of function are not well known. Additionally, it is unclear if single or multiple cell types contribute to the aging process. In the distal lung the alveoli and progenitor cells are embedded within the stroma. Stromal cells provide support, structure, and functional maintenance of surrounding cells. In this project we seek to define the stromal feedback to alveolar stem cells in prematurely aged lungs. We use the inducible mouse model of a rare, monogenic premature aging disease called Hutchinson-Gilford progeria syndrome (HGPS) to identify the specific cellular process or potential processes contributing to the aging phenotype. The lungs of HGPS mutant mice reveal a loss of alveolar gas exchange surface area and an increase in air space. We are able to phenocopy the aging phenotype by modulating the function of distal stroma in the lungs, thus implicating the role of the stroma in maintaining alveolar homeostasis. We propose to investigate the lung stroma as a potential niche for a specific cell type that creates an aging microenvironment for alveolar stem cells. First, we will determine how the prematurely aged stroma affects alveolar progenitor cells in an in vitro co-culture assay. Using with the inducible disease to spatiotemporally activate the HGPS we will then test the potential of the stroma to prematurely age the lungs.